We have examined various parameters related to hypothalamic-pituitary-adrenal axis functioning in euthymic bipolar patients and controls. No differences were found in mean values of urinary free cortisol, plasma cortisol or CSF cortisol. Levels of plasma and CSF proopiomelanocortin were also not different in the two groups. It appears that cortisol dysfunction may be a state but not a trait marker for affective illness. Lumbar punctures have been performed in 23 bipolar patients and a similar number of controls. Ten patients were studied both on and off lithium. Multiple neuroendocrine/biochemical parameters have been measured, but to date, no difference between patients and controls has been found. Lithium effects on HVA and VIP have been noted. The enzyme hexosaminadase A was measured in 30 bipolar patients from our clinic. One patient was found to have significant elevation of the enzyme. Five patients have participated in the antidepressant study of pirbuterol. No sustained antidepressant effect was seen. Ten patients have participated in a study of cognitive functions in affective illness on and off lithium. We expect to test the effect of DGAVP (des-glycyl-arginine vasopressin) in some of these patients. A population of offspring of bipolar patients is currently being assembled for a high risk study of affective disorder. Biological measurements will be done and follow-up initiated over a period of years.